cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions

Cancer cells are known to undergo metabolic reprogramming to sustain survival and rapid proliferation, however, it remains to be fully elucidated how oncogenic lesions coordinate the metabolic switch under various stressed condi- tions. Here we show that deprivation of glucose or glutamine, two majo...

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Published in:	Cell research Vol. 25; no. 4; pp. 429 - 444
Main Authors:	Sun, Linchong, Song, Libing, Wan, Qianfen, Wu, Gongwei, Li, Xinghua, Wang, Yinghui, Wang, Jin, Liu, Zhaoji, Zhong, Xiuying, He, Xiaoping, Shen, Shengqi, Pan, Xin, Li, Ailing, Wang, Yulan, Gao, Ping, Tang, Huiru, Zhang, Huafeng
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-04-2015 Nature Publishing Group
Subjects:	631/443/319 631/80/86 692/699/1503/1607/1610/4029 692/699/1702/295 Animals Apoptosis - genetics Biomedical and Life Sciences Biosynthesis Carcinoma, Hepatocellular - enzymology Carcinoma, Hepatocellular - metabolism Carcinoma, Hepatocellular - pathology Cell Biology Cell Proliferation - genetics Food Deprivation Gene Expression Regulation, Neoplastic Glutathione - biosynthesis Humans Life Sciences Liver Neoplasms - enzymology Liver Neoplasms - metabolism Liver Neoplasms - pathology Metabolic Networks and Pathways - genetics Mice Nucleic acids Nutrients Original original-article Phosphoric Monoester Hydrolases - biosynthesis Phosphoric Monoester Hydrolases - genetics Proto-Oncogene Proteins c-myc - biosynthesis Proto-Oncogene Proteins c-myc - genetics Serine - biosynthesis Serine - genetics SSP Transaminases - biosynthesis Transaminases - genetics 丝氨酸介导激活生物合成途径癌细胞营养缺乏重新编程 SSP cMyc metabolism cancer PSPH
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Summary:	Cancer cells are known to undergo metabolic reprogramming to sustain survival and rapid proliferation, however, it remains to be fully elucidated how oncogenic lesions coordinate the metabolic switch under various stressed condi- tions. Here we show that deprivation of glucose or glutamine, two major nutrition sources for cancer cells, dramat- ically activated serine biosynthesis pathway （SSP） that was accompanied by elevated cMyc expression. We further identified that cMyc stimulated SSP activation by transcriptionally upregulating expression of multiple SSP enzymes. Moreover, we demonstrated that SSP activation facilitated by cMye led to elevated glutathione （GSH） production, cell cycle progression and nucleic acid synthesis, which are essential for cell survival and proliferation especially un- der nutrient-deprived conditions. We further uncovered that phosphoserine phosphatase （PSPH）, the final rate-lim- iting enzyme of the SSP pathway, is critical for cMyc-driven cancer progression both in vitro and in vivo, and impor- tantly, aberrant expression of PSPH is highly correlated with mortality in hepatocellular carcinoma （HCC） patients, suggesting a potential causal relation between this cMyc-regulated enzyme, or SSP activation in general, and cancer development. Taken together, our results reveal that aberrant expression of cMyc leads to the enhanced SSP activa- tion, an essential part of metabolic switch, to facilitate cancer progression under nutrient-deprived conditions.
Bibliography:	cMyc; SSP; metabolism; PSPH; cancer 31-1568/Q Cancer cells are known to undergo metabolic reprogramming to sustain survival and rapid proliferation, however, it remains to be fully elucidated how oncogenic lesions coordinate the metabolic switch under various stressed condi- tions. Here we show that deprivation of glucose or glutamine, two major nutrition sources for cancer cells, dramat- ically activated serine biosynthesis pathway （SSP） that was accompanied by elevated cMyc expression. We further identified that cMyc stimulated SSP activation by transcriptionally upregulating expression of multiple SSP enzymes. Moreover, we demonstrated that SSP activation facilitated by cMye led to elevated glutathione （GSH） production, cell cycle progression and nucleic acid synthesis, which are essential for cell survival and proliferation especially un- der nutrient-deprived conditions. We further uncovered that phosphoserine phosphatase （PSPH）, the final rate-lim- iting enzyme of the SSP pathway, is critical for cMyc-driven cancer progression both in vitro and in vivo, and impor- tantly, aberrant expression of PSPH is highly correlated with mortality in hepatocellular carcinoma （HCC） patients, suggesting a potential causal relation between this cMyc-regulated enzyme, or SSP activation in general, and cancer development. Taken together, our results reveal that aberrant expression of cMyc leads to the enhanced SSP activa- tion, an essential part of metabolic switch, to facilitate cancer progression under nutrient-deprived conditions. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These two authors contributed equally to this work.
ISSN:	1001-0602 1748-7838
DOI:	10.1038/cr.2015.33